Therapeutic effect and mechanism of carboxyamidotriazole on the pulmonary fibrosis of mice induced by bleomycin

Abstract

Objective: To investigate the treatment effect of carboxyamidotriazole (CAI) on bleomycin induced lung fibrosis in mice, and the potential mechanism involved. Methods: A total of 45 mice were divided into three groups randomly. Blank control group (blank group): after a one-time tail vein injection of saline solution 0.2 ml, mice were given polyethylene glycol 400 (PEG-400) 0.1 ml/10 g by gavage once daily for 14 days; the bleomycin group (BLM group): after a one-time tail vein injection of bleomycin 150 mg/kg, mice were given PEG-400 solution 0.1 ml/10 g by gavage once daily for 14 days; CAI group: after a one-time tail vein injection of bleomycin 150 mg/kg, mice were given CAI solution 40 mg/kg by gavage once daily for 14 days. All mice were sacrificed on day 28. Observation index: lung coefficient, survival analysis, pathological section and collagen staining of lung tissue, lung hydroxyproline, Transformation growth factor-β(1)(TGF-β(1)), γ-interferon(IFN-γ), matrix metalloproteinase 9(MMP-9) and tissue inhibitor of matrix metalloproteinasese 1(TIMP-1) content determination in lung homogenate. Results: On day 28 the lung coefficient of mice in BLM group and CAI group was significantly higher than the blank group, and the BLM group was with the highest (all P<0.05). Degree of pulmonary fibrosis in lung tissue pathological specimens (HE staining) was, from heavy to light, BLM group, CAI group, blank group. The content of hydroxyproline in mice lung homogenate was (0.406±0.020) μg/mg in blank group, (0.722±0.118) μg/mg in BLM group, (0.537±0.071) μg/mg CAI group, respectively (all P<0.05). The content of TGF-β(1) in three groups was (15±5), (60±10), (41±10) ng/ml respectively (all P<0.05). The content of IFN-γ in three groups was (47±5), (126±24), (194±34) pg/ml respectively (all P<0.05). The content of TIMP-1 in three groups was (73±6), (369±58), (246±51) ng/ml respectively (all P<0.05). Comparisons of the content of MMP-9 between each group had no significant difference (P>0.05). Conclusions: CAI can reduce lung injury induced by bleomycin in mice. The mechanism of action is related to the effects of CAI on cytokines such as TGF-β(1), IFN-γ, MMP-9 and TIMP-1.